Second-generation PLINK: rising to the challenge of larger and richer datasets

PLINK 1 is a widely used open-source C/C++ toolset for genome-wide association studies (GWAS) and research in population genetics. However, the steady accumulation of data from imputation and whole-genome sequencing studies has exposed a strong need for even faster and more scalable implementations of key functions. In addition, GWAS and population-genetic data now frequently contain probabilistic calls, phase information, and/or multiallelic variants, none of which can be represented by PLINK 1's primary data format. To address these issues, we are developing a second-generation codebase for PLINK. The first major release from this codebase, PLINK 1.9, introduces extensive use of bit-level parallelism, O(sqrt(n))-time/constant-space Hardy-Weinberg equilibrium and Fisher's exact tests, and many other algorithmic improvements. In combination, these changes accelerate most operations by 1-4 orders of magnitude, and allow the program to handle datasets too large to fit in RAM. This will be followed by PLINK 2.0, which will introduce (a) a new data format capable of efficiently representing probabilities, phase, and multiallelic variants, and (b) extensions of many functions to account for the new types of information. The second-generation versions of PLINK will offer dramatic improvements in performance and compatibility. For the first time, users without access to high-end computing resources can perform several essential analyses of the feature-rich and very large genetic datasets coming into use.Comment: 2 figures, 1 additional fil

Reconstructing historical patterns of primary production in Puget Sound using growth increment data from shells of long-lived geoducks (Panopea generosa)

Bottom-up hypotheses predict that changes in primary production affect marine survival of species like Pacific salmon. Long term records of primary production would provide important data to test these predictions. However, direct observations of primary production (in situ fluorometers, water chemistry, and satellite observations of color back-scatter) have relatively short time series (\u3c 30 years). We investigated whether growth increments of geoduck clams (Panopea generosa) are correlated with primary production in different sub-basins of greater Puget Sound. Geoduck are long-lived (older specimens live \u3e100 years), widely distributed throughout the Salish Sea, and deposit annual growth rings in their shells. Shell samples from aged geoducks were by the Washington Department of Fish and Wildlife in four sub-basins within greater Puget Sound (Strait of Jan de Fuca, Southern Strait of Georgia, South Puget Sound, and Central Basin). Geoduck shells from Saratoga passage were provided by the Tulalip Tribe. Using growth indices, the known correlation of growth indices with sea surface temperature and other long-term measurements, and existing basin-level records of temperature and primary production, we modeled historical patterns of primary production in different regions of greater Puget Sound. Analyses show that the relationship between geoduck growth, temperature, and primary production varies between sub-basins, and stable isotope analysis suggests that geoducks may be more than just primary consumers. These issues make reconstruction of a historical record of primary production from growth increments challenging. Nevertheless, analyses suggest that residual growth (after accounting for temperature variation) can explain variation in annual marine survival of local coho and chinook salmon stocks. This indicates the method has promise for retrospective hypothesis testing

Probing for Exoplanets Hiding in Dusty Debris Disks: Disk Imaging, Characterization, and Exploration with HST/STIS Multi-Roll Coronagraphy

Spatially resolved scattered-light images of circumstellar (CS) debris in exoplanetary systems constrain the physical properties and orbits of the dust particles in these systems. They also inform on co-orbiting (but unseen) planets, systemic architectures, and forces perturbing starlight-scattering CS material. Using HST/STIS optical coronagraphy, we have completed the observational phase of a program to study the spatial distribution of dust in ten CS debris systems, and one "mature" protoplanetrary disk all with HST pedigree, using PSF-subtracted multi-roll coronagraphy. These observations probe stellocentric distances > 5 AU for the nearest stars, and simultaneously resolve disk substructures well beyond, corresponding to the giant planet and Kuiper belt regions in our Solar System. They also disclose diffuse very low-surface brightness dust at larger stellocentric distances. We present new results inclusive of fainter disks such as HD92945 confirming, and better revealing, the existence of a narrow inner debris ring within a larger diffuse dust disk. Other disks with ring-like sub-structures, significant asymmetries and complex morphologies include: HD181327 with a posited spray of ejecta from a recent massive collision in an exo-Kuiper belt; HD61005 suggested interacting with the local ISM; HD15115 & HD32297, discussed also in the context of environmental interactions. These disks, and HD15745, suggest debris system evolution cannot be treated in isolation. For AU Mic's edge-on disk, out-of-plane surface brightness asymmetries at > 5 AU may implicate one or more planetary perturbers. Time resolved images of the MP Mus proto-planetary disk provide spatially resolved temporal variability in the disk illumination. These and other new images from our program enable direct inter-comparison of the architectures of these exoplanetary debris systems in the context of our own Solar System.Comment: 109 pages, 43 figures, accepted for publication in the Astronomical Journa

Usability Testing of an Electronic Patient-Reported Outcome System for Survivors of Critical Illness

BACKGROUND: Web-based electronic patient-reported outcomes (ePRO) measures are increasingly used to facilitate patient-centered health assessments. However, it is unknown if ePRO completion is feasible for recently ill intensive care unit (ICU) survivors and their families. OBJECTIVE: To develop and evaluate the usability of a novel ePRO system (ePRO to Support People and Enhance Recovery [ePROSPER]) among ICU survivors and their families within an ongoing clinical trial. METHODS: Paper-based PROs were iteratively adapted to electronic forms (ePROs). Then, the usability of ePROSPER was assessed among 60 patients, their family members, and PRO and programming experts via questionnaires (eg, Systems Usability Scale), "think aloud" open-ended feedback, task completion times, and error rates. RESULTS: Input from patients and their families was used to incorporate user-experience modifications into ePROSPER. This feedback also led to inclusion of automated reminders for questionnaire completion and real-time alerts for staff triggered by high symptom levels. Median usability scores increased over testing cycles from 40 to 73 to 95, nearing the maximum score and showing excellent usability. All users completed ePROSPER within 20 minutes; 87% preferred it to a written version. ePROSPER was then implemented in a clinical trial without data errors. CONCLUSIONS: Automated ePRO systems can be successfully integrated in a post-ICU clinical trial setting. The value of integrating such systems in direct clinical care should be assessed in future studies

Comparison of Magnetic Resonance Feature Tracking for Strain Calculation With Harmonic Phase Imaging Analysis

ObjectivesTo compare a steady-state free precession cine sequence–based technique (feature tracking [FT]) to tagged harmonic phase (HARP) analysis for peak average circumferential myocardial strain (εcc) analysis in a large and heterogeneous population of boys with Duchenne muscular dystrophy (DMD).BackgroundCurrent εcc assessment techniques require cardiac magnetic resonance–tagged imaging sequences, and their analysis is complex. The FT method can readily be performed on standard cine (steady-state free precession) sequences.MethodsWe compared mid-left ventricular whole-slice εcc by the 2 techniques in 191 DMD patients grouped according to age and severity of cardiac dysfunction: group B: DMD patients 10 years and younger with normal ejection fraction (EF); group C: DMD patients older than 10 years with normal EF; group D: DMD patients older than 10 years with reduced EF but negative myocardial delayed enhancement (MDE); group E: DMD patients older than 10 years with reduced EF and positive MDE; and group A: 42 control subjects. Retrospective, offline analysis was performed on matched tagged and steady-state free precession slices.ResultsFor the entire study population (N = 233), mean FT εcc values (−13.3 ± 3.8%) were highly correlated with HARP εcc values (−13.6 ± 3.4%), with a Pearson correlation coefficient of 0.899. The mean εcc of DMD patients determined by HARP (−12.52 ± 2.69%) and FT (−12.16 ± 3.12%) was not significantly different (p = NS). Similarly, the mean εcc of the control subjects by determined HARP (−18.85 ± 1.86) and FT (−18.81 ± 1.83) was not significantly different (p = NS). Excellent correlation between the 2 methods was found among subgroups A through E, except there was no significant difference in strain between groups B and C with FT analysis.ConclusionsFT-based assessment of εcc correlates highly with εcc derived from tagged images in a large DMD patient population with a wide range of cardiac dysfunction and can be performed without additional imaging

Investigating the biological properties of carbohydrate derived fulvic acid (CHD-FA) as a potential novel therapy for the management of oral biofilm infections.

Background: A number of oral diseases, including periodontitis, derive from microbial biofilms and are associated with increased antimicrobial resistance. Despite the widespread use of mouthwashes being used as adjunctive measures to control these biofilms, their prolonged use is not recommended due to various side effects. Therefore, alternative broad-spectrum antimicrobials that minimise these effects are highly sought after. Carbohydrate derived fulvic acid (CHD-FA) is an organic acid which has previously demonstrated to be microbiocidal against Candida albicans biofilms, therefore, the aims of this study were to evaluate the antibacterial activity of CHD-FA against orally derived biofilms and to investigate adjunctive biological effects.<p></p> Methods: Minimum inhibitory concentrations were evaluated for CHD-FA and chlorhexidine (CHX) against a range of oral bacteria using standardised microdilution testing for planktonic and sessile. Scanning electron microscopy was also employed to visualise changes in oral biofilms after antimicrobial treatment. Cytotoxicity of these compounds was assessed against oral epithelial cells, and the effect of CHD-FA on host inflammatory markers was assessed by measuring mRNA and protein expression.<p></p> Results: CHD-FA was highly active against all of the oral bacteria tested, including Porphyromonas gingivalis, with a sessile minimum inhibitory concentration of 0.5%. This concentration was shown to kill multi-species biofilms by approximately 90%, levels comparable to that of chlorhexidine (CHX). In a mammalian cell culture model, pretreatment of epithelial cells with buffered CHD-FA was shown to significantly down-regulate key inflammatory mediators, including interleukin-8 (IL-8), after stimulation with a multi-species biofilm.<p></p> Conclusions: Overall, CHD-FA was shown to possess broad-spectrum antibacterial activity, with a supplementary function of being able to down-regulate inflammation. These properties offer an attractive spectrum of function from a naturally derived compound, which could be used as an alternative topical treatment strategy for oral biofilm diseases. Further studies in vitro and in vivo are required to determine the precise mechanism by which CHD-FA modulates the host immune response.<p></p&gt

Autonomous GN and C for Spacecraft Exploration of Comets and Asteroids

A spacecraft guidance, navigation, and control (GN&C) system is needed to enable a spacecraft to descend to a surface, take a sample using a touch-and-go (TAG) sampling approach, and then safely ascend. At the time of this reporting, a flyable GN&C system that can accomplish these goals is beyond state of the art. This article describes AutoGNC, which is a GN&C system capable of addressing these goals, which has recently been developed and demonstrated to a maturity TRL-5-plus. The AutoGNC solution matures and integrates two previously existing JPL capabilities into a single unified GN&C system. The two capabilities are AutoNAV and GREX. AutoNAV is JPL s current flight navigation system, and is fairly mature with respect to flybys and rendezvous with small bodies, but is lacking capability for close surface proximity operations, sampling, and contact. G-REX is a suite of low-TRL algorithms and capabilities that enables spacecraft operations in close surface proximity and for performing sampling/contact. The development and integration of AutoNAV and G-REX components into AutoGNC provides a single, unified GN&C capability for addressing the autonomy, close-proximity, and sampling/contact aspects of small-body sample return missions. AutoGNC is an integrated capability comprising elements that were developed separately. The main algorithms and component capabilities that have been matured and integrated are autonomy for near-surface operations, terrain-relative navigation (TRN), real-time image-based feedback guidance and control, and six degrees of freedom (6DOF) control of the TAG sampling event. Autonomy is achieved based on an AutoGNC Executive written in Virtual Machine Language (VML) incorporating high-level control, data management, and fault protection. In descending to the surface, the AutoGNC system uses camera images to determine its position and velocity relative to the terrain. This capability for TRN leverages native capabilities of the original AutoNAV system, but required advancements that integrate the separate capabilities for shape modeling, state estimation, image rendering, defining a database of onboard maps, and performing real-time landmark recognition against the stored maps. The ability to use images to guide the spacecraft requires the capability for image-based feedback control. In Auto- GNC, navigation estimates are fed into an onboard guidance and control system that keeps the spacecraft guided along a desired path, as it descends towards its targeted landing or sampling site. Once near the site, AutoGNC achieves a prescribed guidance condition for TAG sampling (position/orientation, velocity), and a prescribed force profile on the sampling end-effector. A dedicated 6DOF TAG control then implements the ascent burn while recovering from sampling disturbances and induced attitude rates. The control also minimizes structural interactions with flexible solar panels and disallows any part of the spacecraft from making contact with the ground (other than the intended end-effector)